Radioligand Therapies and Emerging Targets Drive Innovation in Prostate Cancer Management

The management of metastatic prostate cancer is being reshaped by advancements in radioligand therapies and biomarker-driven strategies, with ongoing research focused on novel targets beyond prostate-specific membrane antigen (PSMA), according to Pedro Barata, MD, MSc, FACP.

“We're talking about different targets and what new targets can be considered for radioligand therapies, [such as] hK2 and STEAP1,” Barata said in an interview with OncLive® following a State of the Science Summit™ on genitourinary cancer, which he chaired. “The future will bring us a lot more data that we'll have to go through and digest to understand the right [roles] for those different therapies as they become available to patients."

These developments, along with the resurgence of interest in previously identified treatments such as the alpha particle-emitting radiotherapy Radium-223 (Xofigo) and the selective pan-AKT inhibitor capivasertib (Truqap), could expand treatment options and refine patient selection in the coming years, he added.

In the interview, Barata highlighted the potential expanding role of radioligand therapies in prostate cancer; discussed emerging targets for future radionuclide therapy development beyond PSMA-targeted radioligand therapies; and emphasized the growing focus on biomarker-driven treatment strategies to refine patient selection and optimize therapeutic outcomes.

Barata is director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, the Miggo Family Chair in Cancer Research at University Hospitals, and an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland, Ohio.

OncLive: How do you anticipate the evolving landscape of radioligand therapy affecting the future management of prostate cancer?

Barata: The [role of] radioligand therapy in prostate cancer is a hot topic. We got the chance to go through the recent data that built upon the prior [2022] FDA approval for lutetium Lu 177 vipivotide tetraxetan [Pluvicto], which we now have available for patients with advanced metastatic castration-resistant prostate cancer [(mCRPC) who have previously received other anticancer therapies, such as androgen receptor pathway inhibition and taxane-based chemotherapy]. We're seeing important datasets from clinical trials being read out [evaluating lutetium Lu 177 vipivotide tetraxetan] in earlier settings of the disease. We also [discussed] other PSMA-based therapies beyond lutetium Lu 177 vipivotide tetraxetan. These other compounds and radioligand therapies are likely to change the landscape and are going to be available for our patients, as well.

We talked about Radium-223, which is a therapy that's been approved for over a decade now with a survival advantage. As the management of mCRPC has changed significantly, Radium-223 has been used in a very small group of patients. Recently, we saw a significant survival advantage with Radium-223 within the [phase 3] PEACE-3 trial [NCT02194842] trial when combined with enzalutamide [Xtandi]. This really brings Radium-223 back into the conversation. [We’re talking about] an alpha particle, radium, in opposition to a beta particle, lutetium.

We are leaving an era and [moving] into a new arena where we're going to have alpha- and beta- [emitting radionuclides, as well as] antibodies. The challenge will be how we're going to use them all. [We will have to figure out which] patients benefit from them. What new targets can be considered for radioligand therapies, like hK2 and STEAP1? The future will bring us a lot more data that we'll have to go through and digest to understand the right [roles] for those different therapies as they become available to patients.

Of the radioligand therapies coming down the pike, are any specific agents particularly intriguing?

This question relates to several factors. One is how effective a therapy can be and whether it can demonstrate that efficacy in the trial that we designed. That relates to many different factors, including how much the marker is overexpressed. Second, does it matter whether you have a small molecule vs an antibody for finding the target? As we're using a therapy like lutetium Lu 177 vipivotide tetraxetan, we will also see antibodies looking to go after PSMA as a target. Third, the setting is relevant. A therapy that can be validated in one particular setting might not be as effective in a different setting for many reasons. [Lastly], can we go beyond PSMA?

We all are biased by the data we’re aware of and our own research goals, but we had the chance to [discuss] an Actinium-225 targeted alpha particle therapy being [targeted] against hK2. From that perspective, I'm encouraged by the data [from a phase 1 trial (NCT04644770)] presented at the 2024 ASCO Annual Meeting on [JNJ-69086420 (JNJ-6420)]. That's a therapy I’ve been paying close attention to.

[Additionally], looking back at PSMA-based therapies, I’ve been paying attention to therapies like [the radio–antibody-drug conjugate] TLX-591, [177Lu rosopatamab tetraxetan]. [It is designed to be delivered] every 2 weeks with 2 different doses in the earlier-line setting in mCRPC. I’m looking forward to seeing more data [with TLX-591] in a phase 3 context [from the ProstACT GLOBAL study (NCT04876651)].

[Overall], the conversation around targeted therapy and biomarker-based approaches in regard to non-chemotherapy or -immunotherapy options will expand beyond PARP inhibitors to include therapies such as capivasertib. That's something else to keep in mind in the months to come.

Moving beyond radioligand therapy, what novel targeted therapies are being explored in metastatic prostate cancer, and how might they shape future treatment approaches?

I would argue [there will be a huge focus] on targeted therapies. This is absolutely going to be the hot topic next year. Why? Because, thus far, our approval for PARP inhibitors in prostate cancer is limited to biomarker-based approvals.

We’ve also [recently] seen data from a drug that [that we had lost] focus on in prostate cancer and have now brought back to life: capivasertib. Capivasertib has been explored in the context of all-comers along with abiraterone acetate [Zytiga] in the mCRPC setting and [in combination with abieraterone acetate and androgen deprivation therapy] in PTEN-deficient tumors. [Previously], there was a signal suggesting efficacy in the group of patients with PTEN deficiency. [Data from the phase 3] CAPItello-281 study [NCT04493853], which was a positive study, [confirmed that] we can leverage this [combination] in PTEN-deficient metastatic hormone-sensitive prostate cancer [mHSPC]. We're going to [continue] talking about it a lot over the next few months because we're talking about [its efficacy in patients who are] PTEN-deficient by immunochemistry, not next-generation sequencing. Capivasertib is a drug that's available in breast cancer, and it might change the landscape of mHSPC.

[Overall], the conversation around targeted therapy and biomarker-based approaches in regard to non-chemotherapy or -immunotherapy options will expand beyond PARP inhibitors to include therapies such as capivasertib. That's something else to keep in mind in the months to come.